IVF Stimulation Protocols – Choosing the Right Approach

In modern IVF, ovarian stimulation is not one-size-fits-all. A variety of protocols are used based on age, ovarian reserve, past response, hormone levels, and individual goals. Here’s a breakdown of the most widely used stimulation strategies.

1. GnRH Antagonist Protocol (Flexible or Fixed Start)

Overview:
Now the most common IVF stimulation protocol in the U.S., the antagonist protocol is appreciated for its flexibility and reduced risk of ovarian hyperstimulation syndrome (OHSS).

How it works:

• Stimulation begins: Day 2 or 3 of cycle with recombinant FSH (Gonal-F®, Follistim®) or hMG (Menopur®).

• GnRH antagonist (e.g., cetrorelix, ganirelix) is introduced on day 5–6 or when the lead follicle reaches ~14 mm.

• Trigger: Final maturation is triggered with either hCG (Pregnyl®, Ovidrel®) or a GnRH agonist (e.g., Lupron®) in high responders.

Advantages:

• Shorter cycle length

• Lower OHSS risk

• Preferred in PCOS patients and egg donors

2. Long GnRH Agonist Protocol (Lupron Downregulation)

Overview:
Once the standard protocol, now used selectively—often for endometriosis or poor responders.

How it works:

• GnRH agonist (e.g., leuprolide acetate): Started in the mid-luteal phase of the cycle prior to stimulation to suppress natural hormone fluctuations.

• Stimulation begins after full pituitary downregulation (~10–14 days).

• Trigger: Typically hCG.

Advantages:

• More synchronized follicular growth

• May improve implantation rates in specific subgroups

Drawbacks:

• Longer and more intense

• Risk of over-suppression in some patients

3. Mini-IVF (Minimal Stimulation IVF)

Overview:
Uses lower doses of medication with the goal of retrieving fewer, higher-quality eggs.

How it works:

• Oral agents like letrozole or Clomid®, sometimes paired with low-dose gonadotropins

• GnRH antagonist or agonist used for suppression

• Often used in natural or lightly medicated cycles

Ideal for:

• Poor responders

• Older patients

• Patients seeking lower-cost or lower-risk cycles

Limitations:

• Fewer eggs retrieved

• Not ideal for embryo banking

4. Natural or Natural Modified Cycle IVF

Overview:
No ovarian stimulation or very minimal drug use. Monitors and retrieves the single naturally selected follicle.

How it works:

• Monitoring via ultrasound and labs

• Possible use of GnRH antagonist late in the cycle

• Trigger with hCG or GnRH agonist

Used when:

• Avoiding medications

• High risk for OHSS

• Specific religious/philosophical beliefs

Limitations:

• Single egg retrieval

• Higher cycle cancellation rate

Tailoring the Protocol

Your reproductive endocrinologist chooses the protocol based on:

• Antral follicle count (AFC) and AMH levels

• Age and previous IVF response

• Diagnosis (e.g., PCOS, diminished ovarian reserve)

• Risk of OHSS

• Patient preference and treatment goals